Year: 2026
Type: preprint
Abstract: Congenital NAD deficiency disorder (CNDD) is a gene × environment disorder caused by disruptions of the kynurenine pathway. To date, CNDD has been associated with biallelic variants in three kynurenine pathway genes: KYNU, HAAO, and NADSYN1 . We identified two sisters with congenital anomalies overlapping with CNDD who have biallelic variants in a gene encoding a different kynurenine pathway enzyme, KMO . The surviving child also has elevated levels of metabolites upstream of KMO with low NAD + levels in plasma, suggesting that KMO deficiency is a novel CNDD. To explore the pathogenicity of KMO deficiency, we generated a global Kmo knockout mouse model ( Kmo -/- ) and utilized dietary interventions to better model human gene × environment interactions. Although Kmo -/- mice are viable and fertile on typical breeder chow, they exhibit elevated serum kynurenine and are functionally vitamin B3-dependent. Under conditions of limited maternal vitamin B3 intake, a greater proportion of Kmo -/- embryos develop congenital anomalies and have significantly lower NAD + levels than Kmo +/- littermates. Exploratory untargeted metabolomics performed in Kmo -/- embryos suggested that NAD + deficiency may perturb the pyrimidine, purine, and pentose phosphate pathways. These findings establish KMO deficiency as a new cause of CNDD and highlight a critical gene × environment interaction influencing NAD metabolism and congenital anomalies.
Source: medRxiv
Authors: Nathalie M. Aceves-Ewing, Nanbing Li-Villarreal, Xiaohui Li, Seema R. Lalani, Jill A. Rosenfeld, Varduhi Petrosyan, Aleksandar Milosavljevic, Angelina Gaspero, Denise G. Lanza, Audrey E. Christiansen, Amrit Koirala, Abu Hena Mostafa Kamal, Nagireddy Putluri, Cristian Coarfa, Bao Tran, Philip L. Lorenzi, Lin Tan, Charul Gijavanekar, Sarah H. Elsea, Emily Lawrence, Hartmut Cuny, Sally L. Dunwoodie, Pengfei Liu, Haonan Zhouyao, Tara L. Rasmussen, Mary E. Dickinson, Carlos A. Bacino, Brendan Lee, Ronit Marom, Undiagnosed Diseases Network, Jason D. Heaney, Chih-Wei Hsu, Lindsay C. Burrage
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: green
Funders: Cancer Prevention and Research Institute of Texas, Victor Chang Cardiac Research Institute, New South Wales Government, National Institutes of Health, Canadian Institutes of Health Research, National Health and Medical Research Council, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: G1270721750, U24-Uncovering the Shared Genetic Origins of Childhood Cancer and Structural Birth Defects Through Enhanced Data Integration and Analysis with the CFDE Data Distillery Knowledge Graph., Orbitrap ID-X Tribrid Mass Spectrometer for Unbiased Global Metabolomics Profiling, Investigating the Role of MFSD14A in TGFbeta Signaling and Cancer-Induced Bone Metastasis, Comprehensive Cancer Epigenomics Core Facility, Proteomics and Metabolomics Core Facility, High Memory High-Performance Computer Cluster for Biomedical Research, SkyScan 1276: Multiscale Micro-CT SystemLaboratory , Towards a Mechanistic Understanding of the Causes of Congenital Heart Disease and Associated Extra-Cardiac Anomalies, G9000010214, G9000111579, G9000177871, G9000263456, Medical Genetics Research Fellowship Program, Understanding the Role of NAD Deficiency in a Mendelian Disorder of Tryptophan Metabolism, Diagnosing the Unknown for Care and Advancing Science (DUCAS)
OpenAlex ID: W7204460025
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